Colorectal cancer is the second leading cause of cancer death in the United States. Conventional therapies including surgery, radiation and chemotherapy have shown limited success with an average 5-year survival of only 8 percent in patients with metastatic disease. Thus recent efforts have focused on cyclooxygenase-2 (COX-2) inhibitors to decrease the risk of colon cancer. These agents reduce the size and frequency of intestinal polyps in adenomatous polyposis coli (APC)-deficient mice and in humans harboring the familial adenomatous polyposis (FAP) mutation. However, cessation of drug therapy results in re-emergence of disease and subsequent mortality. With the goal of achieving durable responses, we propose a therapeutic approach that is antigen-specific and induces long-term tumor immunity. We have chosen to focus on MUC1, an epithelial mucin that is aberrantly expressed in colon cancer. MUC1 is recognized by cytotoxic T lymphocytes and therefore represents a unique target for antigen-specific immunotherapy. The goal of this project is to develop dendritic cell-based vaccines to treat MUCl-expressing adenomas and colon carcinoma in animal models and in colon cancer patients. The hypothesis to be tested is that spontaneously arising MUCl-expressing adenomas or colon carcinoma can be successfully treated using dendritic cell-based vaccines. The Specific Aims of this study are to: 1) develop human MUCl-expressing transgenic mice that spontaneously develop intestinal adenomas and carcinomas 2) develop effective MUCl-specific DC-based vaccines capable of preventing or abrogating adenomatous polyps and carcinoma, 3) conduct pre-clinical in vitro studies using DC-based vaccines to stimulate T cells isolated from colon cancer patients, 4) evaluate the ability of MUCl-specific, DC-based vaccines to induce immunologic responses in colon and pancreatic cancer patients. The MUCl-expressing mice will be generated by crossing the APC-min mouse (Min) or the PI3K-gamma null mouse (PI3K-gamma -/-) with a transgenic mouse expressing human MUC1 (MUC1.Tg). The Min mouse is a strain containing a fully penetrant mutation in the APC tumor suppressor gene leading to the spontaneous development of gastrointestinal adenomas by 3-4 months of age. PI3K-gamma null mice result from targeted disruption of the p1107 catalytic subunit of phosphoinositide-3OH kinase(PI3K-gamma). As with human colorectal cancer, these mice develop spontaneous multifocal adenomas which progress to invasive colorectal adenocarcinomas. The proposed studies are expected to result in the development of novel DC-based vaccines for the prevention and/or treatment of colorectal cancer.